Heart failure is a significant public health problem in contemporary cardiology. Heart failure, estimated to occur in 1% to 4% of the population, increases exponentially with age, so that current demographic trends in industrialized nations predict a dramatic increase in the number of patients with heart failure during coming decades as the populations of these countries grow older.
Heart failure is associated with significant morbidity, high incidence of complications, frequent hospitalization and rising healthcare costs. In the United States alone, an estimated 5 million individuals have a diagnosis of “congestive heart failure”, and an additional 400,000-500,000 new cases are diagnosed annually.
Due to the restricted number of heart donors for heart transplantation and the high cost and drawbacks of mechanical assist devices, a large proportion of end stage heart failure patients need therapies other than current standard modalities. Approximately 25% of patients on waiting lists for heart transplantation die due to limited donor heart availability and more than 50% of all such patients succumb within 5 years of initial diagnosis.
Congestive cardiac failure is caused by a decrease in myocardial contractility due to mechanical overload or by an initial defect in the myocardial fiber. The alteration in diastolic function is inextricably linked with the pathophysiology of cardiac insufficiency. Despite a widely varying and diverse etiology of congestive cardiac failure (e.g. ischemic or idiopathic dilated cardiomyopathies), the pathophysiology is to a great extent constant with the alteration of myocardial contractility as the predominant factor. This contractility defect causes an elevation of the ventricular wall tension resulting in a progressive decline in the contractility of the myocardial fibers. A less-efficient, weakened heart must work harder to pump blood to the body and brain.
In addition to reduced myocardium contractility in combination with enlarged ventricular cavities, heart failure also involves in many cases defects of the heart conduction system resulting in either pump failure or arrhythmia. Approximately one-third of individuals with New York Heart Association (NYHA) Functional Class III/IV heart failure exhibit asynchronous heart rhythm. Further, electrical dyssynchronization between chambers (left or right bundle-branch block) are often found in the heart failure population. Recent studies aimed at correcting these conduction defects by right atrial/left ventricular or right atrial/biventricular pacing have shown beneficial clinical effects of these pacing modalities. Thus, such multisite cardiac pacing to restore appropriate timing between cardiac chambers activities is becoming a valid therapeutic alternative for heart failure patients. However, many patients (up to 40%) experience refractory heart failure due to a persistent myocardial dysfunction one or two years following the initiation of multisite pacing.
The cellular basis for congestive heart failure is based upon a lack of stem cells in the myocardium and the consequent inability of damaged heart cells to undergo repair or divide. Cellular cardiomyoplasty, i.e., transplantation of cells, instead of an entire organ, has a number of attractive attributes and is dependent on an ever expanding understanding of the molecular basis of skeletal myogenesis.
Cellular cardiomyoplasty procedures generally consist of transplanting myogenic cells into the damaged myocardium. Cardiomyoplasty utilizes myogenic cells such as cultured satellite cells (myoblasts), originating from a skeletal muscle biopsy of leg or arms of the same individual into whom the cells are transplanted. Satellite cells are mononucleated cells situated between the sarcolemma and the basal lamina of differentiated muscle fibers. They are thought to be responsible for postnatal growth, muscle fiber repair and regeneration. Another approach for cellular cardiomyoplasty consists of the utilization of bone marrow stem cells, autologous or fetal cardiomyocytes, or smooth muscle cells. However, one of the problems limiting the benefits of cellular cardiomyoplasty is that, even if the myoblasts survive after implantation, they often do not contract spontaneously and hence, they do not improve regional myocardial contractility. Further, the efficiency of cell transplantation engraftment and cellular organization in functional contractile units is often very poor since an efficient electrical coupling with adjacent viable cardiac tissue is difficult to achieve. Thus, there is a need to provide a method for inducing cells to contract spontaneously in order to enhance the contractility of the region into which they are implanted. Electrical activation of skeletal muscle has important clinical applications used in the treatment of a variety of disorders. In cardiology, functional electrostimulation of skeletal muscles has been used to assist ventricular function by way of surgical procedures which generally involve the use of autologous muscle in the form of a latissimus dorsi muscle flap wrapped around the ventricles and electrostimulated in a rhythmic fashion during systole. The success of this operation is due to physiological adaptation of skeletal muscle induced by chronic muscular electrostimulation enabling it to perform cardiac work (“myocardisation” of the latissimus dorsi muscle). Biochemically, there is a metabolic transformation of rapid muscular fibers with glycolytic metabolism, into slow fibers with oxidative metabolism resistant to fatigue. However, such myodardisation is incomplete and the technique remains a largely ineffective mechanism for compensating for damaged myocardium. Thus, there is a need for an effective method for repairing damaged myocardium that results in functioning myocardial cells in the damaged region.